Novel standardized indexes of brainstem auditory evoked potentials for predicting hearing preservation in vestibular schwannomas

Hearing preservation (HP) during vestibular schwannomas (VSs) surgery poses a significant challenge. Although brainstem auditory evoked potentials (BAEPs) on the affected side are commonly employed to monitor cochlear nerve function, their low signal-to-noise ratio (SNR) renders them susceptible to interferences, compromising their reliability. We retrospectively analyzed the data of patients who underwent tumor resection, while binaural brainstem auditory evoked potentials (BAEPs) were simultaneously recorded during surgery. To standardize BAEPs on the affected side, we incorporated the synchronous healthy side as a reference (interval between affected and healthy side ≤ 3 min). A total of 127 patients were enrolled. Comparison of the raw BAEPs data pre- and post-tumor resection revealed that neither V-wave amplitude (Am-V) nor latency (La-V) could serve as reliable predictors of HP simultaneously. However, following standardization, V-wave latency (STIAS-La-V) and amplitude (STIAS-Am-V) emerged as stable predictors of HP. Furthermore, the intraoperative difference in V-wave amplitude (D-Am-V) predicted postoperative HP in patients with preoperative HP and remained predictive after standardization. The utilization of intraoperative synchronous healthy side BAEPs as a reference to eliminate interferences proves to be an effective approach in enhancing the reliability of BAEPs for predicting HP in VSs patients.

Vestibular schwannomas (VSs), accounting for 8% of all intracranial tumors and the most common neoplasm of the Cerebellopontine Angle (CPA), are benign tumors deriving from myelinating Schwann cells of the vestibular branch of the vestibulocochlear (eighth cranial) nerve 1,2 .Microsurgical resection currently stands as the sole radical and frequently preferred treatment option with low mortality rates (< 0.5%) and less than 10% risk of permanent facial weakness 3,4 .However, hearing preservation (HP) has always posed a significant challenge for physicians and patients alike; postoperative HP in VSs is less than one-third compared to over 70% before surgery [5][6][7] .This decline can be primarily attributed to intraoperative cochlear nerve injury, traction and nerve sheath manipulation or vascular ischemia, reliable intraoperative neuromonitoring techniques are essential in avoiding these intraoperative injuries 8 .
Methods traditionally used for intraoperative cochlear nerve monitoring include brainstem auditory evoked potential (BAEPs), cochlear nerve action potential (CNAP), and transotympanic electrocochleography (TT-ECochG) 9 .CNAP can realize continuous real-time monitoring of cochlear nerve function during surgery, but it requires clear anatomical positioning of cochlear nerve and space for placing electrodes, so it is mostly used for VSs with small tumor size (< 1.5 cm) 10,11 .TT-ECochG is an invasive procedure that requires the insertion of recording electrodes through the tympanic membrane to reflect the cochlear nucleus and the external cranial segment of the auditory nerve, so it is mainly used for surgery involving the inner ear and/or cochlea 12 .At present, BAEPs is the most widely used technology for monitoring cochlear nerve function during surgery in the CPA 13,14 .In addition to its simple operation, the prognostic significance of intraoperative BAEPs for HP, particularly during VSs resection, has been widely acknowledged, and distinct indicators of cochlear nerve injury such as the disappearance of stable waves, delay of V wave latency, and decrease of V wave amplitude have been identified [15][16][17] .However, the limited reliability of raw indicators from intraoperative BAEPs arises due to poor signal-to-noise ratio (SNR) and various intraoperative interferences leading to significant variations in sensitivity and specificity for predicting HP across different studies ranging from 37 to 100% 18 .Previous studies have predominantly focused on analyzing BAEPs solely from the affected side while neglecting the healthy side 9,19 .Nevertheless, theoretically incorporating heathy side BAEPs from the synchronously recorded binaural BAEPs as a reference can effectively eliminate interferences.Therefore, this study aims to retrospectively analyze intraoperative BAEPs and standardize those obtained from the affected side by utilizing the healthy side as a reference in order to identify reliable indicators that can predict HP accurately and guide surgeons towards making decisions more conducive to HP during VS resection.

Patient characteristics
A total of 127 patients were enrolled in the present study (Table 1).The mean age of patients at surgery was 48 years (range 15-68 years), with 76 patients (59.8%) being female.Furthermore, 65 patients (51.2%) were found to have tumors on the left side.The mean duration of symptoms (DOS) for VSs was 27.3 months (range 0.5-240 months).The average tumor diameter was measured to be 30.9mm (range 12-76 mm).Among the patient cohort, a total of 79 (62.2%) were classified as Koos grade IV, while smaller proportions exhibited grade III and grade II, consisting of 12 (9.4%)and 26 (20.5%) patients respectively.Goss total tumor resection was performed in all but one case (99.2%).

Intraoperative BAEPs difference
Among the patients with preoperative HP, only 45.2% (38/84) still exhibited HP after surgery.Univariate logistic regression analysis was performed to assess the intraoperative BAEPs difference, revealing that D-Am-V (OR 242.018,P = 0.009) and STD AS -Am-V (OR 54.489, P = 0.02) were predictors of intraoperative HP (Table 4).ROC curve analysis demonstrated an AUC for D-Am-V was 0.634 with a cutoff value of 0.095 μV providing a sensitivity of 34.2% and specificity of 93.5%.The AUC for STD AS -Am-V was 0.695 with a cutoff value of 0 0.001 μV and displayed a sensitivity of 78 0.9% along with specificity of 54 0.3%.However, no significant difference in prediction accuracy between these two indicators was observed (P = 0.334) (Fig. 4).

Discussion
Recent technological developments, particularly the increased availability and accuracy of magnetic resonance imaging (MRI), have increased the detection rate of small VSs (less than 1.5 cm in diameter) 1 .When the tumor shows a slow/null pattern of growth, the wait-and-scan approach is appropriate, but irreversible hearing loss will still progress regardless of imaging evidence of tumor growth 20,21 .Gamma knife radiotherapy may also be considered for small VSs, which is a less invasive option than surgical resection.Although some authors report good short-term functional outcome and satisfactory functional preservation of the facial nerve in up to 95-100% of cases, tumors are not eradicated and disease control requires long-term evaluation 22,23 .Carlson et al. reported a hearing preservation rate of only 23% at 10 years after radiotherapy 24 .Surgical resection remains the only radical treatment.The protection of the cochlear nerve is still a difficulty in surgical resection for nearly 40% of patients suffer from hearing loss due to the injury of cochlear nerve during operation, however, surgical resection can achieve complete resection of the tumor and preserve the anatomical structure of the nerve 6,25 .The incidence of surgery-related non-nerve-related serious complications and facial nerve injury has been effectively controlled, and some studies even suggest that surgical treatment can provide a better chance of long-term hearing preservation than wait-and-scan approach 3,26 .The dilemma of low HP rates following VSs surgery necessitates the implementation of reliable intraoperative cochlear nerve monitoring technology.
BAEPs, the most commonly employed intraoperative neuromonitoring technique for assessing cochlear nerve function during VSs surgery, records I-V waves corresponding to the auditory pathways in the brainstem.Cochlear nerve injury results in delayed latency and decreased amplitude of the V-wave.Most clinical neuroelectrophysiologists involved in BAEPs monitoring during CPA operations consider V-wave latency and amplitude as optimal electrophysiological indicators indicative of cochlear nerve injury caused by the operation 27 .However, previous studies have demonstrated that that these raw indicators lack reliability, a concern also reflected in our analysis findings 9 .Comparing pre-and post-resection raw BAEPs analysis results revealed that neither Am-V Vol:.( 1234567890 www.nature.com/scientificreports/nor La-V can serve as consistent predictors of HP simultaneously, with both exhibiting an AUC value below 0.7.This is primarily blame to the low SNR of BAEPs, rendering them highly susceptible to interference.Noritaka Aihara et al. attempted to mitigate parts of the interferences by utilizing healthy side BAEPs as a reference, resulting in improved prediction accuracy 28 .However, the authors solely obtained healthy side BAEPs within the laboratory setting, which failed to eliminate potential interferences from various internal and external environmental factors during long-term operation.This limitation significantly impacts the reliability of their conclusions; thus, it is recommended to acquire simultaneous healthy side BAEPs during operation. In this study, we recorded binaural BAEPs continuously during the operation, and employed synchronous (interval between affected and healthy side ≤ 3 min) data from the healthy side as a reference for standardizing affected side BAEPs, thereby maximizing interference elimination.www.nature.com/scientificreports/As anticipated, standardized V-wave latency (STI AS -La-V) and amplitude (STI AS -Am-V) demonstrated consistent predictive ability for HP both pre-and post-resection, with an AUC exceeding 0.8 for STI AS -Am-V, indicating its high accuracy in predicting HP.Furthermore, we observed that the intraoperative difference in V-wave amplitude (D-Am-V) predicted postoperative HP in patients with preoperative HP (AUC 0.634) and remained predictive after standardization (STD AS -Am-V) (AUC 0.695).
The waveform of BAEP is usually composed of multiple positive and negative waves, each of which represents the activation of a different part of the auditory pathway.For example, wave I originates from the peripheral part of the cochlear nerve and reflects the action potential of the extracranial segment of the auditory nerve.Wave III is closely related to the electrical activity of the upper olive nucleus.The V-wave originated in inferior colliculus 17 .Usually, the tumor does not directly damage this anatomical structure, but rather causes an effect on the auditory conduction pathway, which is reflected from the pre-resection STIAS-La-III-V extension on the tumor side.www.nature.com/scientificreports/Secondly, this study is a retrospective study, and there may be unmeasurable confounding factors such as patient age, gender and tumor size that may be influencing factors of BAEPs, which need to be further explored in prospective studies.Finally, despite our efforts to standardize procedures and minimize interference, it is important to acknowledge the inherent limitations of BAEPs-in particular, their small amplitude (0.1-0.5 μV) makes repeated measurements (1000-2000 times) necessary on the one hand, resulting in long response delays (1-2 min), and makes BAEPs vulnerable to interference on the other hand.Future research should prioritize the exploration of novel cochlear nerve monitoring techniques that offer enhanced sensitivity and specificity.For instance, Daniele Starnoni et al. successfully monitored cochlear nerve function by directly stimulating the cochlear nerve to evoke postauricular muscle response, yielding promising HP results 30 .The challenge of low HP rates in VSs surgery will be overcome through advancements in neuromonitoring technology.

Patients
We conducted a retrospective review of all VSs patients who underwent surgical resection in our department from January 2018 to June 2022.The clinical, imaging, histopathological, operative reports, and outpatient records were obtained from the hospital information system and follow-up.In this study, we utilized Koos grades for preoperative classification of VSs 31 .The extent of surgical resection was determined based on magnetic resonance imaging (MRI) findings at 3 months postoperation 32,33 .Pure tone average (PTA) and word recognition scores (WRS) were assessed within 1-7 days before surgery and approximately 2 weeks after surgery.The results were evaluated according to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines 34 .Primary outcomes were HP rates, defined as AAO-HNS classic A-C (PTA > 50 dB and WRS ≥ 50%).
Patients were categorized into two subsets: those with HP and those without.All operations were performed via retrosigmoid craniotomy.Patients with bilateral VSs or hearing loss in the unaffected ear were excluded.The study was conducted in accordance with the Declaration of Helsinki, and the study protocol and a waiver of written informed consent were approved by the Clinical Research Center of Tongji Hospital (study approval no.: 202312573) and the Ethics Committee of Tongji Hospital (ethics approval no.:TJ-IRB20210523).

Intraoperative BAEPs
During surgery, continuous monitoring of binaural BAEPs was conducted using a commercially available electrode system (Cadwell Medical, USA).A plug-in earphone was used to give sound, the stimulus sound was broadband clicking sound, and alternating wave stimulation was adopted, the stimulation frequency was 11.9 Hz, the stimulation intensity was 100 dB, the average signal frequency was 2000 times.Recording electrodes: Hypodermic needle electrodes, crown positive electrode (Cz), mastoid negative electrode on both sides (A1, A2).After anesthesia, positioning and fixation of the head frame, BAEP monitoring was performed until the end of surgery.BAEPs indicators encompassed I, II, III, IV, V, I-III, III-V, I-V waves latency, and I and V waves amplitude (measured from positive peak to next negative peak).Key surgical events such as dural incision or beginning/ending of tumor resection were simultaneously marked.Pre-resection BAEPs referred to recordings obtained from the start of surgery until tumor exposure while post-resection BAEPs represented recordings acquired between complete tumor resection and completion of surgery.Data pairing was performed based on affected and healthy sides with a criterion that the recording interval between affected and healthy side should not exceed 3 min.Paired BAEPs were standardized using the healthy side as a reference as follows: Considering that the normal reference is constant, we define the variable in above equation as the Standardized Index for Affected Side (STI AS ), namely: www.nature.com/scientificreports/

Statistical analyses
The statistical analyses were conducted using SPSS statistical package software (version 26.0,IBM Inc., Chicago, US).Continuous variables were presented as mean ± standard deviation, and categorical variables were described as counts (percentage).One-way ANOVA was used for comparison between three or more groups, and paired sample T-test was used for comparison between two groups.Univariate binary logistic regression models were developed to identify predictive variables for HP.HP was considered the dependent variable, and the raw and standardized BAEPs indicators served as independent variables.Variables with a significance level of P ≤ 0.05 in the univariate analysis were included in the stepwise multivariate binary logistic regression model to determine independent predictors of HP.The results are presented with corresponding P values, odds ratios (ORs), and 95% confidence intervals (CIs).Receiver operating characteristic (ROC) curves were generated to evaluate the area under the curve (AUC) and determine cutoff values.ROC curve analysis was performed among different predictors for the same outcome measure.Statistical significance was defined as P < 0.05.

Figure 4 .
Figure 4.A receiver operating characteristic (ROC) curve of intraoperative BAEPs difference predictors of HP, ns No significant difference (P > 0.05).

1 STI 1 D
Standardized intraoperative Difference value in Affected Side BAEPs (STD AS ) are calculated according to following formula: Standardized value of Affected Side = affected side value healthy side value * normal reference value Differencevalue in Affected Side = affected side value − normal reference value Standardized difference value in Affected Side = Standardized value of Affected Side −normal reference value = normal reference value * affected side value healthy side value −AS = Standardized Index of Affected Side = affected side value healthy side value −AS = intraoperative Difference value in Affected Side = affected side value pos -resection −affected side value pre -resection STD AS = Standardizedintraoperative Differencevaluein Affected Side = D AS − (healthy side value pos -resection − healthy side value pre -resection ) https://doi.org/10.1038/s41598-024-58531-8

Table 1 .
Demographics, tumor characteristics, and audiometric outcomes of the study population.

Table 2 .
Univariate and multivariate analyses of BAEPs for predicting preoperative hearing preservation.Significant values are in bold.

Table 3 .
Univariate and multivariate analyses of standardized BAEPs for predicting postoperative hearing preservation.Significant values are in bold.

Table 4 .
Univariate and multivariate analyses of intraoperative BAEPs difference for predicting hearing preservation.Significant values are in bold.